Checkpoint Blockade Rescues the Repressive Effect of Histone Deacetylases Inhibitors on γδ T Cell Function

Area of Science:

• Immunology
• Epigenetics
• Cancer Biology

Background:

• Histone deacetylases (HDAC) are key epigenetic regulators implicated in tumorigenesis.
• HDAC inhibitors are an established cancer treatment modality.
• The impact of HDAC inhibitors on γδ T cell effector functions remains largely unexplored.

Purpose of the Study:

• To investigate the effects of HDAC inhibitors on human γδ T cell effector functions.
• To explore the potential of combining HDAC inhibitors with immune checkpoint blockade for cancer therapy.

Main Methods:

• Treatment of antigen-activated human γδ T cells with HDAC inhibitors.
• Assessment of proliferation, cell cycle progression, transcription factor expression (Eomes, Tbet), and effector molecules (perforin, granzyme B).
• Analysis of immune checkpoint expression (PD-1, PD-L1) and evaluation of PD-1 blockade efficacy.

Main Results:

• HDAC inhibitors reduced γδ T cell proliferation and cell cycle progression.
• Expression of key transcription factors and effector molecules (perforin, granzyme B) decreased upon HDAC inhibitor treatment.
• HDAC inhibitors increased PD-1 and PD-L1 expression, attenuating anti-tumor cytotoxicity, while PD-1 blockade restored effector functions.

Conclusions:

• HDAC inhibitors negatively impact human γδ T cell anti-tumor effector functions.
• Combined HDAC inhibitor and PD-1 blockade therapy enhances γδ T cell anti-tumor activity.
• This study provides a rationale for combinatorial cancer treatment strategies involving HDAC inhibitors and immune checkpoint blockade.